Evaluating the quantity and quality of health economic literature in blinding childhood disorders: a systematic literature review

Background Evidence on the socioeconomic burden associated with childhood visual impairment and blindness (VI/SVIBL) is needed to inform economic evaluations of existing and emerging interventions aimed at protecting or improving vision. This study aimed to evaluate the quantity and quality of literature on resource use and/or costs associated with childhood VI/SVIBL disorders. Methods PUBMED, Web of Science (Ovid), the NHS Economic Evaluation Database and grey literature were searched in November 2020. The PUBMED search was rerun in February 2022. Original articles reporting unique estimates of resource use or cost data on conditions resulting in bilateral VI/SVIBL were eligible for data extraction. Quality assessment (QA) was undertaken using the Drummond checklist adapted for COI studies. Results We identified 31 eligible articles, 27 from the peer-reviewed literature and 4 from the grey literature. 2 reported on resource use and 29 on costs. Cerebral visual impairment (CVI) and optic nerve disorders were not examined in any included studies, whereas ROP was the most frequently examined condition. The quality of studies varied, with economic evaluations (EE) having higher mean QA scores (82%) compared to cost-of-illness (COI) studies (77%). Deficiencies in reporting were seen particularly in the clinical definitions of conditions in EEs and a lacked of discounting and sensitivity analyses in COI studies. Conclusions There is sparse literature on resource use or costs associated with childhood VI disorders. The first step in addressing this important evidence gap is to ensure core VI outcomes are measured in future randomised control trials of interventions as well as cohort studies and are reported as a discrete health outcome.


Introduction
Visual impairment, severe visual impairment and blindness (VI/SVI/BL) is permanent, bilateral visual disability which occurs in 1 per 1000 children in the United Kingdom (UK) [1].Childhood VI/SVI/BL is caused by a constellation of rare disorders.For most children in this setting, onset is in the first year of life and is associated with non-ophthalmic multimorbidity requiring multi-disciplinary specialist clinical management. 1 Whilst childhood VI/SVI/BL is uncommon compared to the prevalence of adult-onset visual disability, the impact is disproportionately magnified by chronic co-morbid conditions, the early impact on development and activities of daily life and the cumulative years lived with impaired vision.
Effective and equitable planning and provision of specialist support, care and education is dependent on information on the socioeconomic impact of visual disability on the child, family, health system and wider society.Understanding the economic impact of childhood visual impairment is important for government decision makers to influence health policy, planning and delivery of key child health and specialist eye services.Economic or cost data is particularly important for the new approval of novel treatments for provision in the National Health Service (NHS) in the UK, where the National Institute for Health and Care Excellence (NICE) mandates the submission of persuasive health economic evidence, specifying preferred methods [2], alongside efficacy and safety data.
The Lancet Global Health Commission on Global Eye Health recently carried out a systematic review of health economic literature of eye health interventions for all ages [3] [4], but it did not report data specifically in children.This impairs our understanding of the health economic landscape in blinding disorders occurring in childhood, an area which remains an important gap in the literature.We report here a systematic literature review to describe the quantity and quality of health economic literature pertaining to childhood visual disability or contributing disorders.

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Methods
We systematically reviewed cost of illness and economic evaluation studies of disorders that cause VI/SVI/BL in childhood in high income settings.This review is reported in line with the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) guidelines [5,6].

Data sources and search strategy
PUBMED, Web of Science (Ovid) and the NHS Economic Evaluation Database (NHS EED, including the CRD, DARE and HTA databases) were searched for peer-reviewed articles on 17 November 2020.Additional articles were added through 'snowballing' of bibliographies and reference lists of eligible articles.A search was also carried out in the Google™ engine as well as in Google scholar™ to identify additional peer-reviewed articles and grey literature, including pertinent cost of illness reports by governmental and non-governmental organisations such as supranational bodies or eye charities.The search strategy used for publications in scientific databases combined key words related to visual impairment, blindness and eye disorders, cost and cost of illness synonyms combined with an amended child filter [7].The full search strategy is presented in Figure S1 alongside the grey literature search strategy.The PUBMED search was rerun on 21 February 2022 to include new studies published since the original search.
The protocol for this review is registered on the Research Registry (reviewregistry1378).

Inclusion criteria
We included any original research article that reported the economic burden, defined as a measure of resource use and/or associated costs, for the diagnosis, treatment, or prevention of a disorder resulting in childhood visual impairment or blindness, defined as any ocular or cerebral disorder contributing to the incidence of childhood VI/SVIBL [1] The disorders resulting in childhood VI/SVI/BL were based on those reported in the only nationally representative epidemiological study of full spectrum childhood VI/SVI/BL in a high income setting [1].To be included, articles had to report a unique estimate of resource use or costs in children (which we defined as the mean or median age of the included population of 18 years or less).There was no restriction on country or language.

Screening & Data extraction
References were exported into the Covidence systematic review software [8] for duplicate removal and for screening.Abstracts were screened independently by two reviewers, and three reviewers screened full texts and extracted data (two reviewers screening 50% articles each and one reviewer screening 100% of articles).Conflicts were addressed through group discussion until a unanimous decision was reached.A standardised data extraction form was used to record data items comprising population specific information (Table S1).Included studies are grouped by anatomical ophthalmic site, following the WHO classification of causes of visual impairment [9].

Methodological (quality) assessment
The checklist published by Molinier et al [10] was used to assess the methodological quality of included studies.This 11-point checklist adapted from the Drummond checklist [11] for COI studies was also used for economic evaluations (Table S2) in the absence of an international consensus on a quality assessment tool for economic studies.Each question in the checklist is of equal weight, and scored as Yes, No or Partially or not specified.The total score was the sum of across all 11 items.
The same checklist was applied to grey literature to provide a framework for quality assessment in the absence of a formal tool assessing for grey literature reports presenting costs.

Synthesis & Analysis
Due to the heterogeneity of included studies (differences in definitions of ophthalmic disorders, cost categories included, resource valuation and geographic setting) we did not carry out a meta-analysis in order to present pooled cost estimates for each ophthalmic condition.Instead we present a narrative review of the studies, following the reporting guidelines for narrative synthesis for systematic reviews without meta-analysis (SWIM) [12].
The main cost measure is presented alongside the cost estimate, most of which are presented as annual, per person costs for each ophthalmic condition, stratified by cost category.Studies reporting costs of visual impairment as an outcome (all-cause VI/SVI/BL) are presented separately, including the level of visual acuity authors used to define visual impairment.Cost estimates were standardised to allow for comparison of costs between studies using different currencies.Standardisation involved first converting the main cost estimate to a base year of 2020 by multiplying by the World Bank consumer price index [13]; a Gross Domestic Product [GDP] deflator) adjusting for inflation, then the Purchasing Power Parity index [14] was applied to convert the reported currency into US dollars (USD). [14]

Results
Our search identified 803 abstracts.Following screening, 31 articles (27 articles from peerreviewed journals and 4 grey literature papers [15][16][17][18]met our inclusion criteria (Figure 1).The full report of one grey literature report could not be found [17], so the summary version of the report was used for data extraction and quality assessment.

Data Sources
The majority of included economic evaluations used data collected in the context of randomised clinical trials and follow up of the original trials (66%, 10/15).Economic evaluations that did not employ resource use and costs data generated from randomised controlled trials, used published data from the literature (n=2 [19,20]) [19,20], expert opinion from ophthalmologists (n=1 [21]) and from hospital records (n=2 [20,22,23]).[19,20] For COI studies, resource use data was collected from a variety of sources from both secondary data sources such as health insurance claims databases (n=2 [18,24]), hospital databases (n=3 [24][25][26]), national figures, e.g.Gross National Product (GNP) per capita (n=1) and primary sources including cost questionnaires to families (based on patient recall) (n=4 [25][26][27][28]).For the 3 case studies [29][30][31]), one employed a daily cost diary completed by the patient over 1 year [30], one used a database from a national resource centre [29], and one used cost estimates from government sources (but these sources were poorly reported [31]).
Grey literature reports used aggregated health system costs or expenditures from national health authorities, surveys and health insurance claims databases as sources of cost data.The lack of national incidence rates of childhood specific visual impairment was evident.Only one report estimated the national burden in the US though this was done in the absence of national rates in children under 12 years.[32]

Study design
Table 1 summarises the study design, age range, sample size and country of included studies.Of the peer-reviewed articles (n=27), 15 were economic evaluations (56%); 9 were cost of illness studies and 3 [29][30][31]were described as 'case studies' that measured or estimated resource use or costs in a small number of children (study sizes ranging from n=3 to n=869).Of the 15 economic evaluations, 6 were cost-utility analyses (CUA), 4 were cost-effectiveness analyses (CEA), 3 were cost-minimization analyses (CMA) [20,21,23], 1 reported outcomes of both a CUA & cost-benefit analysis (CBA) [33] and 1 was a budgetary impact analysis [19].Almost all of these economic evaluations used decision analytic models (14/15), of which 10 used decision tree analysis and 4 used Markov models. 1 study did not specify the 'cost model' used [34].The 9 cost of illness studies were of various designs including use of synthetic cohorts (Table 1), whilst the additional 4 grey literature reports (3 reports commissioned by the third sector [17,18,35], one book chapter [15]) were cost of illness studies using secondary data analysis.

Resource valuation
Costs of medical resource use were acquired from a range of sources comprising reimbursement rates and expenditure data from health insurance providers; national reference hospital costs or charges, or specific hospital department costs; published literature, including published medical association reported statistics; and collection of receipts from interviewed families.Productivity losses were calculated using national average salaries or earnings [15,28,[35][36][37][38] or GDP [26,39,40] or GNP per capita [41].
Methodological quality-The average quality assessment score across all studies was 77% (median score 79%) and scores ranged from 39% to 100%.Quality assessment scores varied by study type, with economic evaluations scoring the highest mean scores at 82%, 77% for cost-of-illness studies, and 56% for case studies.The mean score for 3 of the 4 grey literature reports was 73%.
For economic evaluations, items that had the poorest scores were clear definition of the illness/condition' (8/16 articles were only partially defined), 'discounting of costs' (absent in 7/16) and 'description of epidemiological sources' (partial description only in 5/16).For cost of illness studies, sensitivity analyses were not carried out in the majority of studies (6/8), and the data sources of resource use and cost values were not thoroughly or clearly described in 4/8 articles and discounting of costs only occurred in half of COI studies (4/8).For case studies, both the sources of resource use data as well as the appropriate method of assessment required improvements.
Notably, the reporting of a clear definition of the ophthalmic condition in peer-reviewed articles, occrred in a slightly higher proportion of non-ophthalmic journals compared to ophthalmic journals; 58% vs 53% were reported clearly and 30% vs 40% were partially reported.
Analytic Perspective: The societal perspective was the most common perspective used across studies (n=14), followed by the perspective of the payer (including third party payer) (n=7), healthcare system (n=6), patient perspective (n=2) [28,30], and one article used 'Other' perspective which was from the Government sector.[42] One article did not report the perspective used [41].
Cost outcomes-Cost outcome measures reported in studies were heterogeneous and varied by study type (Table 3.).For economic evaluations, the most common cost outcome was cost per quality adjusted life year (QALY) (9/16), followed by cost savings per child (4/16), incremental net monetary benefit (INMB, 2/16), and incremental cost per treated infant (1/16).
COI studies reported more heterogeneous cost measures, which reflected the specific research question being addressed.Lifetime costs were estimated in 2 studies, one study measured the cost difference between treatments, one study presented costs before, during and after treatment; 2 studies calculated eye/vision specific costs, 1 reporting the mean annual cost of eye involvement in children with Juvenile Idiopathic Arthritis (JIA) [25] and 1 study that reported the marginal annual health cost of visual disturbance or blindness [43] in the fifth year of life in children born premature [43].
Only 6 (all peer-reviewed) of the 31 studies stratified cost or resource use estimates by relevant clinical subgroups or risk factors.4 articles stratified by patient risk factors, included 3 ROP studies using birthweight [19,42,44], and 1 study in preterm infants stratified by gestational age [43]. 1 article stratified costs by disease severity (JIA uveitis [25]) and only 1 study stratified by the presence of comorbidities [43]. 1 study stratified costs by ophthalmic disease subtype, which separated costs for primary childhood glaucoma and secondary childhood glaucoma [45].
Cost categories: 20 studies estimated healthcare costs, 2 estimated non-health costs, 15 estimated indirect costs however only 9 studies presented total indirect costs separately.Of the 15 studies that estimated indirect cost, 4 only measured productivity losses (lost wages or income) associated with caregiving (informal care), 3 only measured productivity losses associated with visual disability (lost wages as an adult) and 6 studies measured both.3 studies did not specify the type of productivity losses measured.Other indirect Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts costs included were [18,32] deadweight losses (taxes and transfers) [18,35] and premature mortality [15].9 studies included costs associated with special education due to VI.
Distribution of ophthalmic conditions: Specific ophthalmic conditions were investigated in the majority of articles (22/31, 71%), whilst 9 investigated all cause VI/SVI/BL (including all four of the grey literature articles).
Figure 2 plots the number of articles identified for each ophthalmic condition represented in the economic literature against the relative burden of each ophthalmic condition in the U.K [1].The size of the bubbles is proportional to the relative burden across all high-income settings, based on global burden of disease data.The dimension of relative global burden was added to allow comparison of U.K data to other similar settings.Figure 2 shows that retinal conditions were most commonly studied (n=14), with retinopathy of prematurity (ROP) the most common specific condition studied [19,26,34,39,40,42,[46][47][48] (9/22, 41%) and well represented in the literature compared to the relative burden of childhood VI/SVI/BL (4%).Three articles examined bilateral congenital or childhood cataract [22,24,28](14%).However, whilst the incidence of ROP and cataract is low in HIC, each is a significant cause of childhood VI/SVI/BL globally due to the high burden in low/middle income countries (LMIC).RPE-65 mediated retinal dystrophy (2/22, 9%), represented the highest burden of any included individual condition (all retinal dystrophies together caused 16% of annual childhood VI).Conversely, childhood uveitis [21,25,49] and congenital toxoplasmosis [20,23,36] (each contributing 14% of articles) were also well represented in the literature in contrast to the relative (proportional) burden.Finally, two articles examined disorders of the globe; 1 in childhood glaucoma (primary and secondary [37]) and 1 in CHARGE syndrome [29] (coloboma, microphthalmos).
No studies examined resource use or costs of vision loss resulting from injury or insult to the visual pathways or cortex (referred to as cerebral visual impairment; CVI), the leading cause of childhood visual impairment in high income settings [1], and a significant cause globally [50].Disorders of the optic nerve and CVI were not represented in the health economic literature and are thus important ophthalmic sites missing from Figure 2 and why proportions do not total to 100%.One study did estimate the marginal healthcare cost of visual comorbidities and blindness in children born preterm, but did not specify what causative disorders were included, so the cost associated specifically with CVI or ROP could not be distinguished.

Time horizon:
For economic evaluations, there were generally two groups of studies, those with a very short time horizon (the period over which health outcomes and costs are calculated), between 8 weeks and 18 months (n=6) and those adopting a lifetime horizon (n=9).For COI studies the time horizon was more heterogeneous and varied between 1 year (n=2), 4 years (n=2) and a lifetime horizon (n=1).
Sensitivity analysis: 93% of economic evaluations (14/15) carried out some form of sensitivity analysis.Deterministic (DSA) as well as probabilistic sensitivity analyses (e.g.Monte Carlo simulation models), were carried out in 7 articles, and a further 7 only carried out DSA (e.g. one or two way sensitivity analyses) (Table 2).This is compared to sensitivity Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts analyses being carried out in only 2/9 COI studies, all of which were limited to one way sensitivity analyses.Grey literature reports were less likely to incorporate sensitivity analysis (2/4) than the peer-reviewed literature, only one report used univariate sensitivity analysis (varied the discount rate only) and another carried out robust sensitivity analysis using both one away and probabilistic methods.

Discussion
In this systematic review of the literature assessing resource use and costs specifically of childhood disorders causing visual disability, we report a scarcity of representative, high quality studies, and heterogeneity of disorder definition, study populations, study metrics and analytic approaches.Retinopathy of prematurity was the most frequent single condition examined, whereas cerebral visual impairment was not represented at all in the evidence base.
This literature review carried out a broad and inclusive systematic search strategy of peer-reviewed literature of childhood ophthalmic conditions that can lead to significant bilateral vision impairment, without restrictions of year of publication, geographical setting or language.Our review also included grey literature, which is an important source for patient information and for advocacy through the third sector.Grey literature can negate the influence of publication bias and help to provide information on the context of healthcare interventions [51].We present key extracted data from studies by anatomical site, using the WHO international classification, for ease of interpretation by clinicians, decision makers and researchers.
Study limitations for this review include, the search strategy, which focussed on resource use or costs of bilateral childhood visual disability in high income settings, and thus excluded articles examining uncorrected refractive error (which carries a significant burden in low income settings) and unilateral conditions such as strabismus (squint) and unilateral cataract.Secondly, due to the significant methodological heterogeneity between studies, particularly the differing definitions of visual impairment used, a meta-analysis could not be carried out.However, this aligns with Cochrane guidance on meta-analysis of cost data, that advises 'extreme caution' when considering a meta-analysis for reviews [52] due to the variation in resource use and costs across settings.
Although the impact of visual disability on the quality of life of the visually impaired child is known to be significant, representative data sources on children and young people remain scarce [53], whilst studies in adult populations are increasing [54].It is promising however, that there is increasing recognition of the importance of child-specific approaches to measuring health related quality of life and assessing interventions for paediatric populations [55] which will hopefully lead to more economic evaluations in this area.
In terms of economic evaluations (EEs), the availability of robust treatment efficacy and resource use data that is collected alongside randomised controlled trials (RCTs) clearly drives the quantity of EEs of blinding childhood disorders, due to the availability of effective treatments and development of novel therapies.Thus, ophthalmic disorders for which Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts treatments are available and have been assessed in RCTs were most frequently studied in the literature, including ROP, uveitis and RPE-65 mediated retinal dystrophy.The latter two conditions reflect the recent availability of new disease-modifying treatments that have been assessed in RCTs.For JIA associated uveitis, the use of a tumour necrosis factor (TNF-α) monoclonal antibody (adalimumab) has been recently shown to be clinically effective in children in the SYCAMORE trial [56], which triggered a cost-utility analysis to assess cost-effectiveness of its use [57].Similarly, the evidence of clinical effectiveness of a novel virus-vector based targeted gene therapy (voretigene neparvovec) for RPE-65 mediated retinal dystrophy in a phase III clinical trial [58] precipitated two economic evaluations included in this study, one in the U.S. [59] and one in the U.K. [60] both using data generated from the trial.
Only one study focussed on an 'untreatable' cause of childhood vision loss, a case study measuring healthcare resource use of children with CHARGE syndrome [29].Whilst 'untreatable' conditions lack interventions aimed at preventing or 'curing' disease, complex interventions aimed at preventing the avoidable lifelong burden of reduced vision have been shown to have a positive impact on outcomes [61].
The notable absence of studies on the economic impact of cerebral visual impairment (CVI) represents a significant gap in the literature, as CVI is one of the leading causes of childhood VI in high-income settings [62,63] including in the U.K. where it is the responsible for almost half (48% [1]) of the burden of childhood visual impairment.This is particularly worrying given the incidence of CVI is likely to increase globally as provision and quality of neonatal care improves and the consequent survival of preterm babies with neurodevelopmental sequelae increases.The absence of CVI studies in the health economic literature reflects the nascence of RCT evidence on both preventative interventions (aimed at the underlying cause of CVI, such as hypoxic ischaemic encephalopathy (HIE)) and interventions focussing on CVI as a functional outcome.A recent scoping review [64] examined the latter type of CVI intervention identifying only 3 RCTs and reported key limitations of the published literature including inconsistency of outcome measures, low quality evidence and small sample size.Published trials of neuroprotective interventions targeted at the underlying causes of CVI, such as HIE, have been inconsistent in their inclusion of visual related outcome measures.For example, only 7 of the 11 trials identified in the Cochrane review of hypothermia reported including visual outcomes [65], with the remaining trials only including visual outcomes subsumed within a composite measure of neurodevelopmental or severe disability or were not included at all [66][67][68][69].
This review therefore highlights that disorders that significant causes of the burden of childhood VI are missing from the health economic literature.Thus increased attention is needed on CVI and 'untreatable' disorders for which tertiary prevention interventions (aimed at reducing the negative impact of established disability) exist, such as habilitation training and low vision aids.As research into neonatal neuroprotective interventions which could prevent CVI expands, it is crucial that visual outcomes are included as core outcomes measures of future trials so these data are available for use in cost-effectiveness models.Childhood visual disability is recognised as a 'sentinel' child health event, [1] and as such, vision should always be a discrete outcome measure in randomised controlled trials Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts and cohort studies of preterm infants, and ophthalmic and vision outcomes should be reported explicitly so that decision models in economic evaluations of interventions can be undertaken.
Aside from the current review, a recent systematic literature review delivered as part of the Lancet Global Health Commission on Global Eye Health [70] evaluated the societal economic impact of the seven leading causes of vision impairment across all ages globally, so included uncorrected refractive error and corneal opacity.This review by Marques et al, identified only 4 peer-reviewed articles involving children and recommended the development of a 'reference case' for eye health; a reference document outlining costing methods to better support decision making [70].Our review supports and extends this recommendation, with findings that highlight the importance of inclusion of specific data items to reduce heterogeneity in methods and resulting cost measures, particularly in cost of illness studies.A second recent review examining economic evaluations in ROP [71] in the U.S., Canada and U.K., included screening studies which the current review excluded.The authors found limited literature (only 9 papers) and found that whilst interventions were highly cost-effective, methodological improvements in reporting of some items was necessary.
Half of the COI and EE studies included in our review used a lifetime time horizon, modelling costs and outcomes across the lifecourse, even though there is a recognised lack of "valid" longitudinal (incidence based) data for conditions during childhood and into adulthood.This lack of long term data starting from childhood is a recognised challenge in constructing lifetime models of disease and economic impact [72].Representative longitudinal data on VI conditions of childhood is therefore needed to provide robust inputs to health economic models and improve the accuracy of findings.In particular for countries with national hospital administrative databases, the routinely collected primary and secondary care resource use data could be harnessed to fill in the gaps in our understanding of specific ophthalmic disorders that affect children, capitalising on the national coverage of such datasets.
In terms of quality, this review highlights the need for better reporting of key components of COI and EEs in childhood VI.Economic evaluations require clear reporting of the definitions of ophthalmic disorders examined and detailed descriptions and transparency in reporting of epidemiological data sources.Both EEs and COIs should incorporate discounting in cost analyses with longer time horizons or report the reasoning for not applying a discount rate to costs.COI studies should include sensitivity analyses to assess the robustness of models used alongside more detailed descriptions of epidemiologic data sources.The quality of grey literature reports could be improved substantially, with more transparent and descriptive reporting of data sources, and explicit statement of the rationale behind the assumptions used.Finally, many studies of childhood VI did not state the visual acuity thresholds used to define severity of visual disability, therefore a final recommendation is for future studies to explicitly state how impairment is classified and the rationale for choosing definitions other than the WHO taxonomy [73].

Conclusion
Our review demonstrates the significant evidence gap in understanding of the health economic burden of childhood vision impairment and identifies the methodological issues that need to be addressed as well as the opportunities to address this evidence gap.This lack of 'visibility' of the health economic impact of childhood visual disability is an important factor in the lower priority given to children in vision and public health policies globally.

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Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts Key points

•
Childhood visual impairment and blindness (VI/SVIBL) results in permanent visual disability in both eyes and affects all aspects of development.As such it is has a significant socio-economic impact on the child, family and society.Health economic data on disorders resulting in childhood VI/SVIBL are necessary for effective and equitable planning and provision of specialist health care and support.
• This is the first systematic literature review to evaluate the quantity and quality of studies reporting resource use and costs associated with disorders that result in childhood visual disability.We found that the health economic literature on childhood VI/SVIBL disorders is sparse.Studies in retinopathy of prematurity (ROP) were most frequently studies in the literature, whereas no studies were carried out in cerebral visual impairment (CVI) and optic nerve disorders.

•
We highlight a significant evidence gap in the health economic literature of childhood VI/SVIBL.It is crucial that visual outcomes are included as core outcome measures of future trials so these data are available for costeffectiveness models.Future economic evaluations and cost-of-illness studies of blinding childhood disorders can be improved by enhanced reporting of key data items and definitions.

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Figure 1 .
Figure 1.PRISMA flow chat of screened and included studies

Figure 2 .
Figure2.Ophthalmic conditions examined in the health economic literature and their relative contribution to burden of childwood visual impairment in high incoming settings †calculated as number cases from ophthalmic disorder/total cases in BCVIS2 1 *size of each bubble is proportionate to the relative burden of each disorder in high income countries.Data used was from Table1.6 Taylor and Hoyt textbook2

Table 1 Summary of included studies, by ophthalmic site and ophthalmic condition examined First Author Year of pub Eye condition/ VI level Country(ies) Paediatric age range * Sample size Study type Study design CHARGE syndrome WHOLE GLOBE AND ANTERIOR SEGMENT
1 *size of each bubble is proportionate to the relative burden of each disorder in high income countries.Data used was from Table 1.6 Taylor and Hoyt textbook 2 Teoh et al.Page 18 Pharmacoeconomics.Author manuscript; available in PMC 2024 March 01.

Table 2 Detailed description of resource valuation, cost components and sensitivity analysis of included studies First Author Resource valuation Cost components (resource use items) T rial data used Sensitivity analysis WHOLE GLOBE AND ANTERIOR SEGMENT CHARGE syndrome
Safety and Cost-effectiveness of Adalimumab in combination with Methotrexate for the treatment of juvenile idiopathic arthritis Unit hospital costs taken from Ministry of Health costing tool, physician fees taken from MoH schedule of benefits.Drug costs taken from national formulary.Hospital costs (surgery, physician visits, anaesthesia, drugs, EUA, glasses fitting), parental out of pocket expenses (parking fees, contact lenses, glasses)Dave  24Reimbursement rates (Medicaid payments) using procedure codes (CPT-4) used for hospital and physician use Medical costs included hospital cataract surgery/procedure (cataract extraction, primary posterior capsulotomy and anterior vitrectomy, anaesthesia, drugs & supplies, Physician follow up) n/a No Wang 28 Costs taken from receipts/invoices from family.Salary loss based on reported monthly salary of family Direct and indirect costs, including hospital treatment, transport, food, lodging, economic losses due to absence from work n/a No UVEA (Uveitis) Cost data on equipment from city's ministry of health (staff salaries) and equipment costs from suppliers.Medical costs of screening and treatment of ROP: staff (ophthalmologist, anaesthesiologist, neonatologists, nurses), equipment for screening and treatment of ROP in NICU (indirect ophthalmoscope, neonatal depressor, indirect diode laser) maintenance and calibration costs of equipment included.Medical costs: hospital admitted services, out of hospital medical services, pharmaceuticals requiring a prescription and research for eye diseases.Non-medical costs: informal care costs, aids and modifications.Indirect costs included productivity losses for parents with children with VI due to unemployment and absenteeism, and deadweight losses (welfare payments).

First author Ophthalmic condition Analytic perspective Time horizon Description of main cost measure Main cost estimate (2020 USD)
Pharmacoeconomics.Author manuscript; available in PMC 2024 March 01.